Begell House Inc.
Critical Reviews™ in Therapeutic Drug Carrier Systems
CRT
0743-4863
18
2
2001
Liposomal Formulations of Cyclosporin A: A Biophysical Approach to Pharmacokinetics and Pharmacodynamics
32
10.1615/CritRevTherDrugCarrierSyst.v18.i2.10
A.
Fahr
Department of Pharmaceutical Technology and Biopharmacy, University of Marburg, Ketzerbach 63, 35032 Marburg, Germany
J.
Seelig
Department of Biophysical Chemistry, Biocenter of the University of Basel, Klin-gelbergstrabe 70, CH-4056 Basel, Switzerland
There are about 20 publications about liposomal formulations of Cyclosporin A (CyA) in the pharmaceutical and preclinical literature. Liposomal formulations were developed in order to reduce the nephrotoxicity of CyA and to increase pharmacological effects. However, conflicting results have been published as to the therapeutic properties of these formulations. This is also true for the change in pharmacokinetics and organ distribution of the liposomally encapsulated CyA as compared to conventionally formulated CyA. Using biophysical methods, it could be shown that CyA is not tightly entrapped in liposomal membranes, despite its high lipophilicity. CyA shows retardation only at high lipid concentrations in blood, following a massive injection of liposomes.This effect may diminish nephrotoxicity, as could be demonstrated by in vitro studies using a model tubule system. The results of these studies can be used to predict the formulation behavior in vivo and to optimize liposomal formulations. When applied in an early phase of the drug formulation process, these types of biophysical experiments can also help minimize animal experiments. However, these basic interaction studies cannot cover all physiological, pharmacological, and toxic effects in animals and humans.
Preparation of Drug Delivery Systems Using Supercritical Fluid Technology
28
10.1615/CritRevTherDrugCarrierSyst.v18.i2.20
Kavitha
Koushik
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198-6025
Uday B.
Kompella
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198-6025
Small changes in temperature and pressure near the critical region induce dramatic changes in the density and solubility of supercritical fluids, thereby facilitating the use of environmentally benign agents such as CO2 for their solvent and antisolvent properties in processing a wide variety of materials. While supercritical fluid technologies have been in commercial use in the food and chromatography industries for several years, only recently has this technology made inroads in the formulation of drug delivery systems. This review summarizes some of the recent applications of supercritical fluid technology in the preparation of drug delivery systems. Drugs containing polymeric particles, plain drug particles, solute-containing liposomes, and inclusion complexes of drug and carrier have been formulated using this technology. Also, polymer separation using this technology is enabling the selection of a pure fraction of a polymer, thereby allowing a more precise control of drug release from polymeric delivery systems.
Insulin Self-Association and the Relationship to Pharmacokinetics and Pharmacodynamics
64
10.1615/CritRevTherDrugCarrierSyst.v18.i2.30
Michael R.
DeFelippis
Research Technologies and Product Development, The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285
Ronald E.
Chance
Research Technologies and Product Development, The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; Retired
Bruce H.
Frank
Research Technologies and Product Development, The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; Retired
The treatment of type 1 diabetes requires multiple, daily injections of insulin. While many improvements involving formulation adjustments have been made in an attempt to optimize therapy, clinical experience indicates that the commercially available insulin preparations used for treatment have significant limitations. One principal deficiency relates to poor simulation of the physiological insulin secretion pattern, making achieving normalization of blood glucose concentrations difficult. Endogenous insulin secretion in nondiabetic subjects is characterized by a pulsatile profile that displays multiple, meal-stimulated phases and low basal concentrations between meals and overnight. Optimal diabetes therapy, therefore, requires insulin preparations that display a rapid onset of action with corresponding rapid clearance to provide for meal ingestion as well as preparations that can maintain a sustained, peakless profile for basal requirements. Recent efforts in pharmaceutical research have used the concept of rational-based design of the insulin molecule in an attempt to produce preparations that display more ideal pharmacological profiles. Using detailed structural information obtained from X-ray crystallographic studies to guide design strategies and exploit the nonrestrictive synthetic capabilities of recombinant DNA technology, researchers have prepared a number of insulin analogs that display a reduced propensity towards self-association. Clinical evaluations have shown that these so called "monomeric" analogs better mimic the meal-stimulated pharmacokinetics of insulin secretion observed in nondiabetics. Two monomeric insulin analog preparations have successfully obtained regulatory approval and are now commercially available. Efforts to produce optimized basal-acting insulin analogs have lagged behind. While some of these analogs have been engineered using recombinant DNA technology, design strategies in many cases exploit physicochemical properties of insulin other than self-association. One basal insulin analog has recently received regulatory approval. This paper reviews insulin self-association and its relationship to pharmacokinetics and pharmacodynamics. Particular emphasis is placed on the approaches used to manipulate self-assembly resulting in mealtime insulin analogs that display optimal pharmacological properties. Other design strategies used to develop improved basal insulin preparations are also considered.